Role of p120-catenin in oral squamous cell carcinoma

p120-连环蛋白在口腔鳞状细胞癌中的作用

• 批准号: 7737094
• 负责人: Zhongjian Xie
• 金额: $ 23.25万
• 依托单位: NORTHERN CALIFORNIA INSTITUTE/RES/EDU
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-08-01 至 2011-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7737094
• 关键词: 1,2-diacylglycerol; 1-Phosphatidylinositol 3-Kinase; Address; Adhesions; Biology; Calcium; Carcinogens; Carcinoma; Cell Adhesion Molecules; Cell Proliferation; Cell membrane; Cell-Cell Adhesion; Cells; Chemosensitization; Clinical; Complex; Cytoplasmic Protein; Data; Development; Diagnosis; Diglycerides; Disease; E-Cadherin; E-Cadherin Staining Method; Epidermal Growth Factor Receptor; Epithelial; Epithelium; Equilibrium; Goals; Human; Hydrolysis; Inositol; Knockout Mice; Location; Malignant Epithelial Cell; Malignant Neoplasms; Mediating; Mus; Neoplasm Metastasis; Nitroquinolines; Oncogene Activation; Oncogenes; Outcome; Oxides; Pathway interactions; Phosphatidylinositol 4,5-Diphosphate; Phosphatidylinositols; Phospholipase C; Play; Prevention; Preventive; Receptor Signaling; Recruitment Activity; Regulation; Role; Signal Pathway; Signal Transduction; Sublingual Region; Therapeutic; Tongue; Tumor Suppressor Proteins; advanced disease; cancer cell; carcinogenesis; chemical carcinogen; extracellular; insight; keratinocyte; keratinocyte differentiation; lymph nodes; mouth squamous cell carcinoma; phosphatidylinositol 3,4,5-triphosphate; public health relevance; tripolyphosphate; tumor; tumor initiation

DESCRIPTION (provided by applicant): P120-catenin is a cytoplasmic protein directly associated with the cell-cell adhesion molecule Ecadherin in the plasma membrane. Its expression is frequently reduced in carcinoma including oral squamous cell carcinoma (OSCC), but the relationship between p120-catenin and human cancers is unclear. Previous studies have shown that p120-catenin plays important roles in the regulation of proliferation and differentiation of keratinocytes, roles requiring activation of phospholipase C-?1 (PLC-?1). In these cells, extracellular calcium induces the formation of a p120-catenin dependent E-cadherin/catenin complex that recruits and activates phosphatidylinositol 3-kinase (PI3K). PI3K converts phosphatidylinositol 4,5-bisphosphate (PIP2) to phosphatidylinositol 3,4,5-triphosphate (PIP3). PIP3 in the plasma membrane then recruits and activates PLC-?1, which by hydrolyzing PIP2 to inositol 1,4,5-triphosphate (IP3) and diacylglycerol (DAG) causes an increase in intracellular calcium leading to keratinocyte differentiation. Expression of p120-catenin is reduced in carcinoma cells. Many studies, including ours, have also shown that PLC-?1 mediates epidermal growth factor receptor (EGFR) induced cell proliferation. Expression of PLC-?1 has been found to be elevated in carcinoma cells. These observations have led us to the hypothesis that p120-catenin functions as a tumor suppressor inhibiting OSCC formation by competing with the oncogene EGFR for PLC-?1 activation. The mechanism and location of PLC-?1 activation determine the delicate balance between differentiation and proliferation of keratinocytes. To address this hypothesis, we propose the following specific aims: (1) Determine whether mice lacking p120-catenin are predisposed to carcinogen-induced OSCC formation. (2) Determine whether p120-catenin and EGFR signaling pathways regulate each other. These studies will uncover a tumor suppressor role for p120-catenin in OSCC and provide assessment of predisposing conditions to carcinogenesis, better prevention, better diagnosis, and better treatment of the disease. PUBLIC HEALTH RELEVANCE: p120-catenin is a cytoplasmic protein directly associated with the cell-cell adhesion molecule E- cadherin in the plasma membrane and its expression is frequently reduced in carcinoma cells including oral squamous cell carcinoma (OSCC), but the relationship between p120-catenin and human cancers is unclear. These studies will determine the tumor suppressor role for p120-catenin and provide insight into the mechanism by which p120-catenin protects cells from the development of OSCC. Understanding this mechanism will bring the possibility of new preventive and therapeutic options for OSCC.

描述（由申请人提供）：P120-连环蛋白是一种与质膜中的细胞间粘附分子叶钙粘蛋白直接相关的细胞质蛋白。它的表达在包括口腔鳞状细胞癌 (OSCC) 在内的癌症中经常降低，但 p120-连环蛋白与人类癌症之间的关系尚不清楚。先前的研究表明，p120-连环蛋白在角质形成细胞的增殖和分化调节中发挥重要作用，其作用需要激活磷脂酶C-α1（PLC-α1）。在这些细胞中，细胞外钙诱导 p120-连环蛋白依赖性 E-钙粘蛋白/连环蛋白复合物的形成，该复合物招募并激活磷脂酰肌醇 3-激酶 (PI3K)。 PI3K 将磷脂酰肌醇 4,5-二磷酸 (PIP2) 转化为 磷脂酰肌醇 3,4,5-三磷酸 (PIP3)。然后质膜中的 PIP3 招募并激活 PLC-α1，PLC-α1 通过将 PIP2 水解为肌醇 1,4,5-三磷酸 (IP3) 和二酰甘油 (DAG) 导致细胞内钙增加，从而导致角质形成细胞分化。癌细胞中 p120-连环蛋白的表达降低。许多研究，包括我们的研究，也表明 PLC-?1 介导表皮生长因子受体 (EGFR) 诱导的细胞增殖。已发现癌细胞中 PLC-β1 的表达升高。这些观察结果使我们得出这样的假设：p120-连环蛋白作为肿瘤抑制剂发挥作用，通过与癌基因 EGFR 竞争 PLC-α1 的激活来抑制 OSCC 的形成。 PLC-β1激活的机制和位置决定了角质形成细胞的分化和增殖之间的微妙平衡。为了解决这一假设，我们提出以下具体目标：（1）确定缺乏 p120-连环蛋白的小鼠是否容易发生致癌物诱导的 OSCC 形成。 (2)确定p120-catenin和EGFR信号通路是否相互调节。这些研究将揭示 p120-连环蛋白在 OSCC 中的肿瘤抑制作用，并提供对致癌诱发条件的评估，更好地评估 预防、更好地诊断和更好地治疗疾病。公共卫生相关性：p120-连环蛋白是一种细胞质蛋白，与质膜中的细胞间粘附分子 E-钙粘蛋白直接相关，其表达在包括口腔鳞状细胞癌 (OSCC) 在内的癌细胞中经常降低，但 p120 与 p120 之间的关系-连环蛋白和人类癌症的关系尚不清楚。这些研究将确定 p120-连环蛋白的肿瘤抑制作用，并深入了解 p120-连环蛋白保护细胞免受 OSCC 发展的机制。了解这一机制将为口腔鳞癌带来新的预防和治疗选择的可能性。